TGF-ß1 and TNF-α differentially regulate Twist1 mediated resistance towards BRAF/MEK inhibition in melanoma.
Pigment Cell Melanoma Res
; 26(6): 912-6, 2013 Nov.
Article
en En
| MEDLINE
| ID: mdl-23848983
ABSTRACT
Resistance to BRAF and MEK inhibition is a common phenomenon in melanoma. Cytokines and transcription factors have been attributed to contribute to the loss of sensitivity towards these inhibitors. Here, we show that transforming growth factor (TGF)-ß1 if combined with PLX4032, a BRAF inhibitor, or GSK1120212, a MEK inhibitor, substantially increased cell death in BRAF-mutant melanoma cell lines. This increase was based on the combined regulatory decrease in Twist1, an antiapoptotic protein. Overexpression or silencing of Twist1 attenuated or aggravated induction of apoptosis through PLX4032 or GSK1120212, respectively. Exposure to tumour necrosis factor (TNF)-α, however, led to increased Twist1 levels and oppositional decrease in cell death if exposed to PLX4032 or GSK1120212. This increase in drug resistance again depended on Twist1 levels. Our studies suggest that Twist1 as a common downstream target of multiple signalling cascades plays a crucial role in mediating drug resistance to BRAF- and MEK-targeted molecular inhibitors.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Proteínas Nucleares
/
Factor de Necrosis Tumoral alfa
/
Resistencia a Antineoplásicos
/
Quinasas de Proteína Quinasa Activadas por Mitógenos
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Proteínas Proto-Oncogénicas B-raf
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Proteína 1 Relacionada con Twist
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Factor de Crecimiento Transformador beta1
/
Melanoma
Límite:
Humans
Idioma:
En
Revista:
Pigment Cell Melanoma Res
Asunto de la revista:
NEOPLASIAS
Año:
2013
Tipo del documento:
Article
País de afiliación:
Austria